DESCRIPTION: This renewal proposal is based on the hypothesis that carbon monoxide, CO, is a previously unrecognized messenger molecule from vascular cells that exerts important autocrine and paracrine actions on vessels and platelets. The objective of the application is to document that CO is a novel, distinctive and biologically active autacoid from smooth muscle and endothelium that arises due to specific humoral and hemodynamic stimuli. Three aims are: 1. Determine the biological effects of endogenous CO on platelet function and smooth muscle proliferation in vivo and in vitro; 2.Examine the molecular basis of enzyme control between the CO and nitric oxide NO systems, defining the effect of NO on CO production by heme oxygenase and conversely the effect of CO on NO production by NO synthase; and 3. Elucidate the molecular mechanisms of regulation of CO and NO release (from smooth muscle and endothelium) by shear stress and cyclic strain. The goal is to establish CO as an important vascular cell messenger molecule that modulates blood fluidity and may prove to be a target for therapy of vascular disorders.